CA2020253A1 - Phenylethenyl compounds having retinoid-like activity - Google Patents

Phenylethenyl compounds having retinoid-like activity

Info

Publication number
CA2020253A1
CA2020253A1 CA002020253A CA2020253A CA2020253A1 CA 2020253 A1 CA2020253 A1 CA 2020253A1 CA 002020253 A CA002020253 A CA 002020253A CA 2020253 A CA2020253 A CA 2020253A CA 2020253 A1 CA2020253 A1 CA 2020253A1
Authority
CA
Canada
Prior art keywords
methyl
compound
compounds
phenyl
ethenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA002020253A
Other languages
French (fr)
Inventor
Roshantha A. S. Chandraratna
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Allergan Inc
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of CA2020253A1 publication Critical patent/CA2020253A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4056—Esters of arylalkanephosphonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/01—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and halogen atoms, or nitro or nitroso groups bound to the same carbon skeleton
    • C07C323/09—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and halogen atoms, or nitro or nitroso groups bound to the same carbon skeleton having sulfur atoms of thio groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/22—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/215—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring having unsaturation outside the six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/30—Compounds having groups
    • C07C43/315—Compounds having groups containing oxygen atoms singly bound to carbon atoms not being acetal carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
    • C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
    • C07C45/292—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups with chromium derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/20—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms
    • C07C47/277—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/28—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups having unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/94—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Immunology (AREA)
  • Dermatology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

ABSTRACT
Compounds of the following formula, useful for treating diseas-es affected by retinoids, are disclosed herein.

Description

2~2~2~3 ..

PHE~IYLETHE~YL COMPOUNI~S HAVING RETINOID-LIKE ACl'IVI'rY
2 This invention relates to novel eompounds having retinoid-lilce activity, pharmaceutieal compositions comprising those compounds and the methods of using tbem.
~mmarv of the InvcntiQn-The compounds of this invention are represented by thefollowing formula:
Formula I

R2~0--(CH2)n-A
z_y R4 It ~2 in which:
Rl, R2, R3 and R4 are hydrogen, lower allcyl, halogen or 4 lower allcoxy;
~ Rs is hydrogen or lower allcyl;
16 Y iS oxygen or sulfur;
Z is 1-10 carbon straight or branched alkyl or 2-10 carbon straight or branched unsaturated allcyl;
n is 0-5; and A is H, -COOH or a pharmaceutically acceptable salt, ester or 2~ amide thereof, -CH20H or an ether or ester derivative, or -CHO or an 22 acetal derivative, or -COR6 or a Icetal derivative where R6 is -(CH2)mCH3 where m is 0-4.
This invention also relates to a pharmaceutical composition u comprising a compound of formula I in admixture with a ~6 pharmaceut;cally acceptable excipient.
27 In addition, this invention relates to the use of the compounds ~ 6757 of formula I for treating dermatoses, such as acne, Darier's disease, psoriasis, icthyosis, eczema, atopie dermatitis and epithelial caneers ~ The~e eompounds are also useful in the treatment of arthritic 4 diseases and other immunologieal disorders (e g, lupus erythematosus), in promoting wound healing and in tre~ting the dry eye syndrome, and in preventing or reversing the effeets of sun 7 damage to slcin In another aspect, this invention relates to the process for mal~ing a compound of formula I, which process comprises reacting a compound of formula II with a compound of formula I~I in the presence of sodium hydride Il . .
R, R5 z ~ P--(CH2)n-A

R3 CH2PO(OC2H5)2 ,. .
I~
II III
7 where Rl R2 R3,R4 R5 Y and Z are as defined hereabove;
con~erting the ester of formula I to an acid; and to prepare compounds in which n is l-S, homologating a compound of the for-mula R2~G--(CH2)nCOOH

r where n is 0-4, or 2~2~2~

conver~ing an acid of formula I ~o an ester; or converting an acid of formula I to an amide; or reducing an acid of formula I to an alcohol of aldehyde; or converting an aleohol of formula I to an ether or ester; or oxidizing an alcohol of formula I to an aldehyde; or converting an aldehyde of formula I to an acetal.
General Embodim Defini~jQ~
The term "ester" as used here refers to and co~ers any compound falling within the definition of that term as classically used in organic chemistry. It includes organic and inorganic esters.
Where A is -COOH, this tcrm covers the products derived from J3 treatment of this function with alcohols or thioalcohols. Wherc the 4 ester is derived from compounds where A is -CH20H, this term covers compounds derived from organic acids capable of forming esters ineluding phosphorous-based and sulfur-bascd acids, or 7 compounds of the formula -CH20COR whcrc R is any substituted or unsubstituted aliphatie, aromatic, hctcroaromatic or aliphatic-aromatie group.
Prcfcrrcd cstcrs arc derivcd from thc saturatcd aliphatic alcohols or acids of tcn or fcwcr carbon atoms or thc cyclic or saturatcd aliphatic cyclic alcohols and acids of 5 to 10 carbon atoms.
Particularly prcferred aliphatic esters are those derived from lower alkyl acids and alcohols. Here, and wherever else used, lower alkyl means having 1-6 carbon atoms. Also preferred are thc phenyl or lowcr alkyphenyl esters.
r~ The term "lower allcyl" means an allcyl radical of 1 to 6 carbon atoms.
Amides has thc mcaning classically accordcd that tcrm in x organic ehcmistry. In this instancc it includcs the unsubstitutcd amidcs and all aliphatic and aromatic mono- and di-substitutcd amidcs. Prcfcrred amides are the mono- and di-substitutcd amides - 2~2~2~

derived from the saturated aliphatic radicals of ten or fewer carbon atoms or the cyclic or saturated aliphatic-cyclic radicals of S to 10 carbon atoms. Particularly preferred amides are those derived from substitutet and unsubstituted lower alkyl amines. Al~o preferred S are mono- and di-substituted amides derived from the substituted ~ and unsubstituted phenyl or lower allcylphenyl amines.
7 Unsubstituted amides are also preferred.
Acetals includes the radicals of ~he formula -CK wbere K is (-OR)2. Here, R is lower all~yl. Also, K may be -OR60- where R6 is ~o lower allcyl of 2-S carbon atoms, straight chain or branched.
A pharmaceutically acceptable salt may be prepared for any compounds in this invention having a functionality capablc of forming such salt, for e~ample an acid functionality. A
pharmaceutically acceptable salt is any salt which retains the activity of the parent compound and does not impart any deleterious or untoward effect on the subject to which it is administercd and in ~7 the eontext in which it is administered.
Pharmaceutically aceeptable salts may be derivçt from organic or inorganic b~ses. The salt may be a mono or polyvalent ion. Of partieular inte-..st are the inorganic ions, sodium, potassium, calcium, 21 and magnesium. Organic salts may be made with amines, n partieularly ammonium salts such as mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromcthamine and similar molccules.
2~ The prcferred compounds of this invention are those of 26 formula I wherc thc (CH2) -A substitucnt is para to thc cthenyl 27 chain on the benzene ring; n is 0, 1 or 2; and A is -COOH, an alkali metal salt or organic amine salt, or a lower allcyl es~cr, or -CH20H
and the lower alkyl esters thereof. Particularly preferred com-x pounds are:
~ ethyl 4-[E-2-methyl-2-(4-(3-methyl-2-butenoxy)phenyl)ethc-12 nyllbcnZOatC;

- . .
- ; . ~ : -2~2s~3 ethyl 4-[E-2-(4-3-methyl-2-thiobutcnyl)phcnyl)cthenyllben-zoa~e.
4- [E-2-mcthyl-2(4-(3-mcthyl-2-butcno%y)phcnyl)cthc-ny1]benzoic acid, and 4-[E-2-(4-(3-mcthyl-2-thiobutenyl)phenyl)cthenyl~be~zoic ' acid.
The compounds of this invention may be atministered systcmically or topically, depending OD such considerations as the condition to be treatcd, need for sitc-specific treatmcnt, quantity of ~o drug to be administered, and numcrous othcr considerations.
In the treatmcns of dermatoses, it will generally bc prcferred 2 to administer thc drug topically, though in certain cases such as trca~mcnt of severc cystic acne or psoriasis, oral administration may also bc used. Any common topical formulation such as a solution, suspcnsion, gcl, ointment, or salvc and the like may be used.
Preparation of such topical formulations arc wcll described in the art 7 of pharmaceutical formulations as exemplifiet, for examplc, " .B~m~on's Pha~naceutical Science. Edition 17, Mack Publishing l~ Company, Easton, Pennsylvania. For topical application, thes~
compounds could also be administcred as a powdcr or spray, 21 particularly in acrosol form. If ~hc drug is to be administercd systemically, it may bc confectcd as a powder, pill, tablct or thc like, or as a syrup or clixir suitablc for oral administration. For intravcnous or intraperitoncal administration, the compound will bc u prcpared as a solution or suspcnsion capable of being administcrcd by injection. In ccrtain cases, it may bc uscful to formulate thcsc compounds in suppository form or as an extended release formulation for dcposit under the slcin or intramuscular injection.
Other medicaments can be added to such topical formulation for such secondary purposes as trcating skin dryncss; providing protection against light; other mcdications for trcating dcrmatoscs;
mcdicamcnts for prevcnting infection, reducing irritation, . .
' ~
, :

202~253 ~ inflammation and the lilce.
2 Treatment of dermatoses or any other indications Icnown or ~ disco~ered to be susceptible to treatment by retinoic acid-lilte 4 compounds will be effected by administration of the therapeutically effective dose of one or more compounds of the insta~t inve~tion. A
therapeutic concentration will be that concentration whieh effects 7 reduction of the particular condition, or retards its e~pan~ion. In certain instances, the compound potentially may be used in a prophylactic manner to prevent ODSCt of a partieular eonditio~.
A useful therapeutic or prophylactic concentration will vary from condition to condition and in certain instances may vary with the severity of the condition being treated and the patient's susceptibility to treatment. Accordingly, no single concentration will be uniformly useful, but will require modification depending on the particularities of the disease being treated. Such concentrations can be arrived at through routine experimentation. However, it is 17 antieipated that in the treatment of, for example, acne, or similar dermatoses, that a formulation containing between 0.01 and 1.0 l~ milligrams per milliliter of formulat ~n will constitu. a x therapeutically effective concentratio~. for total applicàtion. If administered systemically, an amount between 0.01 and 5 mg per kg per day of body weight would be expected to effect a therapeutic result in the treatment of many diseases for which these compounds are useful.
The retinoic acid-like activity of these compounds is confirmed through the classic measure of reeinoic acid activity involving the ~ effects of retinoic acid on ornithine decarbo~ylase. The original work Y on the correlation between retinoic acid and decrease in cell proliferation was done by Verma ~ Boutwell, Cancer Research.1~77.
x 37. 2196-2201. That reference discloses that ornithine decarboxylase (ODC) activity increased precedent to polyamine biosynthesis. It has been established elsewhere that increases in .. . .

.: ' "
, ~ ' '' .
: :
. ~ ~

- 202~3 polyamine synthesis can be eorrelated or assoeiated with cellular proliferation. Thus, if ODC activity eould be inhibited, eell ~ hyperproliferation could be modulated. Although all cases for ODC
4 activity increases are unlc~own, it is known that 12-0-tetradecanoylphorbol-13-acetate (TPA) induces ODC ~cti~ity.
~ Retinoie aeid inhibi~s this induetion of ODC aeti~rity by TP~. An assay 7 essentially following the procedure set out in Cancer~,:
1662-1670, 1975 msy be used to demonstrate inhibition of TPA
induction of ODC by compounds of this invention.
Pre~aration of Cornpounds It is antieipated that the compounds of this invention can be 12 made by a number of different synthetic ehemical pathways. To illustrate this invention, there is here laid out a series of steps which 4 will provide the eompounds of formula I when sueh synthesis is followed in tone and in spirit. The synthetic chemist will readily appreeiate that the eonditions set out here are speeifie embodiments whieh ean be generalized to any and all of the compounds represented by formula I.
Compounds of formula I are prepar-d as per the following flow chart.
,.

R, R5 R2 ~o + p cooC2H5 Z-Y~R4 CH2PO(OC2H5)2 \

2Q2~2~3 R2~,C--COOC2Hs R2~,~3--COOH

' 2-Y R4 R3 \ Homologatlon \

R2~'0 CH2)n-COOH

These acids may be converted to the salts, esters and amides.
~ Also the acids may be converted to alcohols which can then be con-7 verted to aldehydes and ~etones which can then be convcrted to cor-responding acetals and Icetals.
According to the above proccdure, a diethyl (4-carboethoxybenzyl~phosphonate is reacted with a 4-alkoxy (or allcylthio) benza1dehyde or a 4-allcoxy (or alltylthio)-phenyl lower alltyl ~etone in the presence of sodium hydride to give the ethyl benzoate compound of this invention.
Hydrolysis of the ester group by standard procedures gives the , . . .
, - . . ' ' : ' .
,~ - `, 2~2~2~3 corresponding acid (formula V). The hydrolysis may be accomplished by basie saponification with an alkali metal base. For example, an ester of formula IV may be dissolved in 8 polar solvent sueh as an alltanol, preferably under an inert atmospbere at room temperature with about a three molar excess of base, for e%ample~
~ potassium hydroxide. The solution is stirred for an e%~ended period 7 of time, between lS and 20 hours, eooled, aeidified and the hydrolysate recovered by conventional means.
To prepare the eompounds of formula VI where n is 1-5, the ID benzoic acid compounds of formula V are subjeeted to homologation ~ by suecessive treatment using the Arndt-Eistert or similar proce-12 dure.
The pharmaceutically acceptable salts, esters and amides represented by formula I are obtainable from the acids of formula V.
Esterifieation is aeeomplished by refluxing the aeid in a solution l' of the appropriate aleohol in the presenee of thionyl ehloride or by 17 reacting the acid and the appropriate aleohol in the presence of 1,3-dieyelohexylcarbodiimide and 4-dimethylaminopyridine. The ester is reeovered and ~ rified by eonventional means.
Salts are prepared .,y reacting the aeid with an appropriate 21 base by standard proeedures.
22 The amide may be formed by any appropriate amidation 2~ means known in the art. One way to prepare soch compounds is to Y first mal~e an aeid chloride and then treat that compound with 2~ ammonium hydroxide or an appropriate amine. For example, the acid is treated wi~h an aleoholic solution of base such as ethanolic 27 KOH (in approximately a 10% molar excess) and reacted at room temperature for about 1/2 hour. The solvent is removed and the residue tal~en up in an organic solvent such as ether, treated with a ~o dialkyl formamide and then a 10-fold exeess of oxalyl chloride. This is all effeeted at a reduced temperature between about -10C and 2 +10C. The last mentioned solution is then stirret at the reduced temperature for 1-4 hours, preferably 2 hours. Solven~ remo~ral pro~ides a residue which is talcen up ia an inert organic sol~ent such ' as benzene, cooled to about 0C and treated with eoneentrated ammonium hydroxite. The resulting mixture is ~tirred ~t a reduced temperature for 1-4 hours. The product is reco~ered by con~entional means.
7 Alcohols are made by converting the eorresponding aeids to the aeid chloride as deseribed above and then redueiDg the aeid ehloride with sodium borohydride (Mareh, Ibid, pg. 1124), whieh gi~es the corresponding aleohols. Al~ylating these alcohols with appropriate alkyl halides under Williamson reaction conditions (March, Ibid, pg.
12 357) gives the corresponding ethers.
Aldehydes can be prepared from the corresponding primary aleohols using mild oxidizing agents sueh as exemplified by ' pyridinium diehromate in methylene chloride (Corey, E.~., Sehmidt, G., Tet. Lett.. 399,197~!.
7 Aeetals ean be prepared from the eorresponding aldehyde by the method described in March, Ibid, p. 810.
The fol wing examples ar~ set out to illustrate the invention, not to limit its ~cope.
Exam~1e 1 :1~ 4-Carboethoxy-benzylbromid~
To a stirred solution of 16.09 g (78 mmol) of 1,3-dicyclohexylcarbodiimide (Aldrich) in 100 ml methylene chloride was added a suspension of 15.4 g (71 mmol) of 4-carboxybenzylbromide in 100 ml methylene chloride and then 4.9 n g (106.5 mmol) of absolute ethanol and 0.81 g (7.1 mmol) of 4-dimethylaminopyridine. A further 50 ml of methylene chloride was added to the reaction mixture and mixture heated at reflux for 2 o h. The mixture was allowed to eool to room temperature and the resultant white precipitate removed by filtration. The filtrate was washed with water, dried (MgS04) and then eoncentrated in-vaeuo 202~2~3 to give the title compound as a colorless oil which crystallized on standing. PMR (CI)C13): ~1.39 (3H, t, J~ 7.2 Hz), 4.38 (2H, q, J- 7.2 Hz), ' 4.S0 (2H, s), 7.4S (2H, d, 1~ 7.7 Hz), 8.03 (2H, d, J~ 7.7 Hz).

l~iethyl (4-carboethoxybcnzyl!~hosDhonat~
A mixture of 11.8 g (48 mmol) of 4-carboethoxybeDzylbromide 7 and 12.0 g (72 mmo1) of freshly distilled triethylpbosphite was placed in a flaslc fittet witb an argon ;nlet ant a dry-ice eooled trap.
A continuous stream of argon was passed over tbe stirred reaction ~o mixture and mi~ture heated at 120-C for 3 hours at which time no further ethyl bromide was being formet. The residue was purified 12 by vacuum distillation to give the title compound as a colorless oil, BP s 170C/0.35 mm). PMR (CDC13): ~1.23 (6H, t, J- 7.1 Hz), 1.39 ~4 (3H, t, J~ 6.9 Hz), 3.21 (2H, d, J- 22.1 Hz), 4.02 (4H, m), 4.37 (2H, q, J
" ~ 7.S Hz), 7.38 (2H, t, J ~ 7.9 Hz), 8.00 (2H, d, J - 7.9 Hz).
" Exampl~
~7 4-(3-Methyl-2-buteno2~yl-acetophenonç
~' A mixture of 7.S g (SS.l mmol) of 4-hydroxyacetophenone, 7.6 I' g (S5 ' mmol) of potassium carbonate and 150 ml of acetone was heated at reflux under argon for 1.5 hours. This mixture was then 21 cooled in an ice-bath and treated slowly with a solution of 8.7 g (58.4 mmol) of 4-bromo-2~methyl-2-butene in 5 ml of acetone. The cooling bath was removed and mixture heated at reflux for 17 hours.
The reaction mix~ure was coolcd to room temperature and the solvent removed in-vacuo. The residue was treated with 100 ml water and extracted with 2 x 100 ml of ether. The ether extracts were combined and washed successively with 2 ~c 50 ml of 10%
NaOH, 50 ml of water and 75 ml of saturated NaC1 and then dried (MgSO4). Solvent was removed in-vacuo and residue purified by Kugelrohr distillation (100C, 0.25 mm) to give the title compound as a white solid.
,2 PMR (CDC13): ~1.76 (3H, s), 1.81 (3H, s), 2.S3 (3H, s), 4.58 (2H, .

2~2~2~

d, J ~ 7.0 Hz), S.S0 (IH, t. J- 7.0 Hz), 6.94 (2H, d, J~ 8.0 Hz), 7.92 (2H, t, J - 8.0 Hz).
E~amDle 4 4 Et}Ul 4-[E-2-methy1-2-r4-(3-methyl-2-buteno~y~
phenyllethenyllbenzoa~e and Ethyl 4-TZ-2-methyl-2-,~4-(3-methyl-2-butcnoxy)phcnyllcthenyllben~oats.
200 mg of 60% NaH in mineral oil (5 mmol)under ~rgon was washed successively with three 2 ml portions of he~anes. 20 ml of the dry tetrahydrofuran (THF) aod 40 mg of lS-Crown-S (Aldrich) were then added to the reaction vessel and mixture cooled to 0C
The reaction mixture was then treated with a solution of 1.0247 g 12 (S.0614 mmol) of 4-(3-methyl-2-butenoxy)-acetophenone and 1.508g (5.0218 mmol) of diethyl(4-carboethoxybenzyl)-phosphonate in 10 ml dry THF. The cooling bath was removed and the reaction mixture stirred at room temperature for 60 hours. The mixture was then ~reated with 100 ml water and extracted with 3 % 7S ml ether.
7 The ether extracts were combined and washed successi~ely with 2 x 2S ml of 10% sodium bisulphite and S0 ml saturated NaCl and then lt dried (MgSO4). Solvent was removed in-~acuo and the residual oil purified by flash chromatography (silica; 10% ethyl acetate in hexanes) to give a mixture of the E and Z isomers. The mixture of E/Z isomers was separated by high pressure liquid chromatography (Whatman Partisil 10 M-9; 3% ethyl acetate in hexanes) to gi~c thc E-isomer as a white solid and the Z-isomer as a pale yellow oil.
E PMR (CDC13): ~1.43 (3H, t, 1 ~ 7.4 Hz), 1.79 (3H, s), 1.84 (3H, s), 2.30 (3H, s), 4.41 (2H, q, 27 J- 7.4 Hz), 4.56 (2H, d, J~ 6.6 Hz), 5.54 (lH, t, J~ 6.6 Hz), 6.82 (lH, s) 6.95 (2H, d, J~ 8.1 Hz), 7.43 (2H, d, J~ 8.1 Hz), 7.49 (2H, d, J- 8.9 Hz), 8.07 (2H, d, J- 8.9 Hz).
PMR (CDC13); ~1.37 (3H, t, J- 7.2 Hz), 1.77 n (3H, s), 1.83 (3H, s), 2.23 (3H, s), 4.34 (2H, q, .

202~2~3 ~ ~ 7.2 Hz), 4.S2 (2H, d, J- 6.9 Hz), S.S3 (lH, t, J~ 6.9 Hz), 6.47 91H, s), 6.8S (2H, d, J- 8.4 Hz), 7.0S, (2H, d, J - 7.7 Hz), 7.10 (2H, t, - 8.4 Hz), 7.81 (2H, t, J- 7.7 Hz).
Examgl~
4-(3-Mcthyl-2-thiobutenyl~bromobenzcn~
A mi~cturc of 12.8 g (67.7 mmol) of 4-bsomothiophenol and ' 2.7g (67.7 mmol) of sodium hydroxide in S0 ml acetone was heatct at reflux undcr argon for 2.S hours. Tbe reflu~cing mi~turc was thcn treatcd dropwisc with a solution of 10.0 g (67.1 mmol) of 4-bromo-2-methyl-2-butcnc in 10 ml acetonc and thc mixturc 1 heated at reflux for a further 24 hours. The mixture was then cooled ~' and solvent rcmovet in-vacuo. The residue was treated with 50 ml watcr and e~ctracted with 3 x 75 ml ether.
'~ The ether extracts were combincd and washcd successively with 3 x 30 ml of S% NaOH, S0 ml of water and S0 ml of saturated ~7 NaCI and then dried (MgSO4). Solvcnt was then removcd in-vacuo ant the residual oil purificd by Kugelrohr distillation (70C, 0.1 mm) to give the title compound as a colorless oil.
PMR (CDC13): 81.58 (3H, s),1.70 (3H, s),3.5 (2H, ~ J ~ 8.3 Hz), 7.36 (2H, d, J~ 8.3 Hz).
Examplc 6 4-(3-Met~h,,~l-2-thiobuterlyl~-benzaldehvde To a solution of 1.9517 g (7.S886 mmol) of 4-(3-methyl-2-thiobutenyl)-bromobenzenc in 25 ml dry cther Y at -78C under argon, was added dropwise 9.0 ml of 1.7 M (15.3 mmol) tert-butyllithium in pentane. The reaction mixture was stirred at -78C for 3 hours and then treated dropwise with a solution of 885.7 mg (12.12 mmol) of dimethylformamide in 6 ml dry e~her. The cooling bath was then removcd and the mixture stirrcd at room tcmperature for 26 bours, thcn coolcd to 0C and treated with 75 ml of saturated NH4CI. This mixturc was thcn , ~ .

2~21~2~

extracted with 3 ~c 75 ml ether. The ether extracts were combined and washed suceessively with saturated NaHCO3 and saturated NaCI
solutions and then dried (MgSO4). The ~olvent was then removed in-vacuo and residue purified by flash chromatography (silica; 10*
' ethyl acetate in he%anes) followed by Kugelrohr distillation (90C, ~ 0.25 mm) to give the title compound as a colorless oil.
7 PMR (CDC13: ~1.74 (3H, s), 1.76 (3H, s), 3.66 (2H, d, J~ 6.9 Hz), 5.33 ~lH, t, J- 6.9 Hz), 7.3S (2H, d, J- 8.8 Hz~, 7.76 (2H, d~ J- 8.8 Hz), 9.92 (lH, s).
~o Exam~le 7 Ethyl 4-(E-2-(4-(3-methy1-2-thiobutentl~I~henvl)-ethenvl) ~2 benzoate One hundred sixty milligrams of 60% NaH in mineral oil (4 4 mmol) under argon was washed successively with three 2 ml portions of hexane. 15 ml of dry THF and 70 mg of IS-Crown-S
- were then added to the reaction vessel and mixture cooled to 0C.
17 The reaetion mixture was then treated with a solution of 773.3 mg (3.7483 mmol) of 4-(3-methyl-2-thiobutenyl)-benzaldehyde and - 1.1282 g (3.757 mmol) of diethyl-(4-carboethoxybenzyl)-phospho-nate in 10 ml of dry THF. The cooling bath was then removed and 2t the reaction mixture stirred at room temperature for 2 hours.
The mixture was then treated with 100 ml water and extracted with 3 x 75 ml ether. The ether extracts were combined and washed successively with 2 x 25 ml of 10% sodium bisulphite and 50 ml of saturated NaCI and then dried (MgSO4). Solvent was removed ~ in-vacuo and the residue purified by flash chromatography (silica;
2, 10% ethyl acetate in hexanes) to give a mixture of the E and Z
~ isomers of the title compound. A portion of this mixture was D recrystallized from an ether/hexanes mixture to give pure E-isomer as a white crystalline solid.
PMR (CDC13): ~1.45 (3H, t, J- 7.1 Hz), 1.67 (3H, s), 1.77 (3H, s), 3.62 (2H, d, l - 7.8 Hz), 4.42 (2H, q, J- 7.1 Hz), S.36 (lH, t, J- 7.8 Hz), ~2~3 7.12 (IH, d, 1~16.S Hz), 7.21 (IH, d, J- 16.5 Hz), 7.3S (2H, d, J- 8.2 ~ Hz), 7.48 (2H, d, J- 8.2 Hz), 7.S8 (2H, d, J- 8.1 Hz), 8.07 (2H, d, J- 8.1 ) Hz).
E~ampl~ 8 By the procedure of Examp1es 1-4 using the appropriately 2, 3, ~ S and/or 6-substituted 4-carboethoxybenzylbromide as ~t~r~ing 7 materials, the following compounds (iD thc E and Z iso~erie forms) may bc made:
ethyl 2-chloro-4-(2-methyl-2-(4-(3~methyl-2-butenoxy) phenyl)ethenyl)bcnzoate, ethyl 3,S-dimethyl-4-(2-methyl-2-(4-(3-methyl-2 2-butcnoxy)phenyl)cthenyl)benzoate, ethyl 3,S-dimethoxy-4-(2-methyl-2-(4-3-methyl-2-butenoxy)phenyl)cthenyl)bcnzoatc, ~' ethyl 2,6-diehloro-4-(2-methyl-2-(4-3-methyl-2-butenoxy)phenyl)cthenyl)bcnzoate, or ~7 ethyl 2,3,S,6-tetramethoxy-4-(2-methyl-2-(4-(3-methyl-2-butenoxy)phenyl)ethenyl)bcnzoatc.
E~mple 9 Procccding by thc proccss lf Examplcs 1-4, using 2-carbocthoxybcnzylbromide and 3-carboethoxybenzylbromide in ~ place of the corresponding 4-carboethoxy compound, the following products (in the E and Z isomeric forms) are obtained:
ethyl 2-(2-methyl-2-4(4-~3-methyl-2-butenoxy) phcnyl)ethcnyl)bcnzoatc, and ~5 ethyl 3-(2-mcthyl-2-(4-(3-methyl-2-butcnoxy) phenyl)ethcnyl) benzoatc.
Example 1~
By the procedure of Example 1, reacting x 4-hydroxyacetophenone with methyl bromide, butyl bromidc, . . .

- , ~

2~2~%~3 ' decyl bromide ,or 2 6-bromo-2-hexene ~ gives the following intermediates:
4 4-methoxyacetophenone 4-butoxyacetophenone 4-decyloxyacetophenone 4-(4-hexenoxy)acetophenone which, when reacted with die~hyl-(4-carboetho~ybenzyl)-phospho-nate by the procedure of Example 4, gives the following products as the E and Z isomers:
ethyl 4-(2-methyl-2-(4-methoxyphenyl)ethenyl) ~2 bcnzoatc.
ethyl 4-(2-methyl-2-(4-butoxyphenyl)ethenyl) benzoate, ethyl 4-(2-methyl-2-(4-decyloxyphenyl)-ethenyl)benzoate, or ethyl 4-(2-methyl-2-1;4-(4-hcxcnyJoxy) phenyl)ethenyl)benzoate.
The E and Z isomers can be separated by conventional means as described in Example 4.
Example 11 To a solution of 100 mg of ethyl 4-(E-2-methyl-2-(4-(3-methyl-2-butenoxy)phenyl)ethenyl)-benzoate in 3 ml of cthanol undcr argon is added dropwise a solution of SO mg of potassium hydroxide in 3 ml of ethanol and 1 ml of water. The mi~ture is stirred at room temperature for 18 hours, cooled and acidified with 3N hydrochloric acid. The resulting precipitate is dissolved in e~her, thc ether solution washed with saturated aqueous sodium chloride and concentrated to give a solid which is recrystallized from aqueous mcthanol to givc 4-(E-2-methyl-2-(4-(3-methyl-2-butenoxy) phenyl)ethcnyl) benzoic acid.

.

2~2~2~3 Example 12 A mixture of SO mg of 4-(2-methyl-2-(-4-(3-4 metbyl-2-butenoxy)phenyl)ethenyl)benzoic acid and ethanolic S potassium hytroxide is stirred at room temperature for O.S hours ~ and sol~ent is remo~ed in-~acuo. The residue is dissolved iD S ml 7 ether, treated with 1 drop of dimethylformamide, cooled to 0, then treated with 150 mg of oxalyl chloride. After ~tirring at 0 for 2 hours, the mixture is filtered, the residue is washed with etber and the combined organic solutions concentrated. The residue is dissolved in benzene, cooled to 0. ant treated dropwise with 2 ml of J~ concentrated aqueous ammonium hydroxide. The mixture is stirred at 0 for 2 hours, diluted with 30 ml water and extracted with ether.
The ether extract is washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in-vacuo to give 4-(2-methyl-2(4-(3-methyl-2-butenoxy)phenyl)ethenyl) ~7 benzamide.
- Using methylamine in place of ammonium hydroxide, the product is N-methyl-4-(2-methyl-2-(4-~o (3-methyl-2-butenoxy)phenyl)ethenyl)benzamide.
Example 13 4-(2-Methyl-2-(4-(3-methyl-2-butenoxy)phenyl) ethenyl)benzoic acid is converted to the corresponding benzoyl chloride by treating the potassium salt of the acid with oxalyl chloride as described in Example 12. The benzoyl chloride is reacted with diazomethane and the resulting diazoketone is decomposed 2~ using silver oxide catalyst in methanol to give methyl 4-(2-methyl-2-(4-(3-methyl-2-butenoxy)phenyl)ethenyl)phçnylace-tate.
x By the procedure of Example 11, the methyl phenylacetate is hydrolyzed to give 4-(2-methyl-2-(4-(3-methyl-2-butenoxy)phenyl)ethenyl)-phenylacetic acid.

2a2~25~

Using this phenylacetic acid in the above procedurcs givcs methyl 4-(2-methyl-2-(4-(3-methyl-2-butenoxy)phenyl)-~ ethenyl)3-phenylpropionate and the corresponding phenylpropionic 4 acit.
Similarly, the following compounds are obtained:
methyl 4-(2-methyl-2-(4-(3-methyl-2-buteno~y) phenyl)ethenyl)-4-phenylbutanoate, methyl 4-(2-methyl-2-(4-(3-methyl-2-butenoxy) phenyl)ethenyl)-5-phenylpentanoate, and methyl 4-(2-methyl-2-(4-(3-methyl-2-buteno~y) phenyl)ethenyl)-6-phenylhexanoate.
Hydrolysis of these methyl esters gives the corresponding phenylbutanoic acid, phenylpentanoic acid and phçnylhexanoic acid ~4 compounds.
,. ~Q~
Ethyl 4-(E~-2-(4-(3-methyl-2-thiobutenyl)phenyl)-~7 ethenyl)benzoate is hydrolyzed by the procedure of Example 11 togive 4-(E-2-(4-(3-methyl-2-thiobutenyl)-- phenyl)ethenyl)benzoic acid.
This benzoic acid is converted to the correspon lng benzoylchloride as described in Example 12 and the benzoylchloride is reduced with sodium borohydride by standard procedures (J.
March, "Advanced Or~anic Chemistryn, 2nd Edition, McGraw-Hill Boolc Company, pg. 1124) to give 4-(E-2-(4-(3-methyl-2-thiobutenyl)-phenyl)ethenyl)benzyl alcohol.
~eacting the benzyl alcohol with methyl chloride under 27 Williamson reaction conditions (March, Ibid, pg. 357) gives methyl 4-(E-2-(4-(3-methyl-2-thiobutenyl)phenyl)-ethenyl)benzyl ether.
x Similarly, using 4-(E-2-methyl-2-(4-(3-methyl-2-butenoxy)-phenyl)ethenyl)benzoic acid in procedures described above the n following are obtained:

20~2~3 4-(E-2-me~hyl-2-(4-(3-me~hyl-2-bu~eno~cy)phenyl) ethenyl)benzyl slcohol, and metbyl 4-(E-2-methyl-2-(4-(3-methyl-2-buteno~
phenyl)ethenyl) benzyl ether.
Example 15 Treatment of the benzyl alcohol compounds prep~lred as in Example 14 with pyridinium dichromate in methylene ehloride by standard procedures gives:
4-(E-2-(4-~3-methyl-2-thiobutenyl)-pbe-nyl~ethenyl)benzaldehyde, and .1 4-(E-methyl-2-(4-(3-me~hyl-2-butenoxy)phenyl) 12 ethenyl)benzaldehyde.
' Exam~le 16 - The benzaldehyde compounds, prepared as in Example 15, in ethanol solution are treated with hydrogen ehloride gas by standard - procedures to give:
. 4-(E-2~(4-(3-methyl-2-thiobutenyl)-phe-- nyl)ethenyl~benzaldehyde, diethyl acetal, and 1. 4(E-2-methyl-2-(4-(-methyl-2-buten ;y)phenyl) ethenyl)benzaldehyde, diethyl acetal.
Reaction of the benzaldehyde compounds with ethylene glycol using an acid catalyst gives the corresponding cyclic ethylene acetals.
Examl?le 17 Preferably, these compounds may be administered topically using various formulations. Such formulation may be as follows:
,6 _ n In~redient Wei~ht/Percent Solution Retinoid0. 1 o BHT 0 1 Alcohol USP 58.0 Polyethylene Glycol 400 NF 41.8 - : ~

' . . . ~ . . . .

2~2~3 5~.
' RctiDoit 0.1 BHT 0. 1 Alcohol USP 97.8 Hydroxypropyl Ccllulose 2.0 ~:

Claims (15)

1. A compound of the formula:

in which:
R1,R2,R3 and R4 arc hydrogen, lower alkyl, halogen or lower alkoxy;
R5 is hydrogen or lower alkyl;
Y is oxygen or sulfur;
Z is 1-10 carbon straight or branched alkyl or 2-10 carbon straight or branched unsaturated alkyl;
n is 0-5; and A is H, -COOH or a pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or an ether or ester derivative, or -CHO or an acetal derivative, or -COP or a ketal derivative where R6 is -(CH2)mCH3 where m is 0 4.
2. The compound of claim 1 where Y is 0.
3. A compound of claim 2 where n is 0, 1 or 2.
4. A compound of claim 3 where A is COOH or an ester or amide, or a pharmaceutically acceptable salt thereof.
5. A compound of claim 4 in which R1, R2, R3 and R4 arc hydrogen .
6. A compound of claim 4 in which R1, R2, R3 and R4 are hydrogen and R5 is methyl.
7. A compound of claim 4 in which Z-Y- is 3-methyl-2-butenoxy.
8. The compound of claim 1 where Y is S.
9. A compound of claim 8 where n is 0, 1 or 2.
10. A compound of claim 9 where A is COOH or an ester or amide, or a pharmaceutically acceptable salt thereof.
11. A compound of claim 10 in which R1,R2,R3 and R4 are hydrogen.
12. A compound of claim 10 in which R1,R2,R3 ant R4 are hydrogen and R5 is methyl.
13. A compound of claim 10 in which Z-Y- is 3-methyl-2-thiobutenyl.
14. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1.
15. A method for treating psoriasis in a mammal which method comprises administering, alone or with a pharmaceutically acceptable excipient, a therapeutically effective amount of a compound of claim 1.
CA002020253A 1989-07-26 1990-06-29 Phenylethenyl compounds having retinoid-like activity Abandoned CA2020253A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US385,626 1989-07-26
US07/385,626 US4992468A (en) 1989-07-26 1989-07-26 Phenylethenyl compounds having retinoid-like activity

Publications (1)

Publication Number Publication Date
CA2020253A1 true CA2020253A1 (en) 1991-01-27

Family

ID=23522205

Family Applications (1)

Application Number Title Priority Date Filing Date
CA002020253A Abandoned CA2020253A1 (en) 1989-07-26 1990-06-29 Phenylethenyl compounds having retinoid-like activity

Country Status (8)

Country Link
US (1) US4992468A (en)
EP (1) EP0410742B1 (en)
JP (1) JPH0381240A (en)
AT (1) ATE123754T1 (en)
AU (1) AU638037B2 (en)
CA (1) CA2020253A1 (en)
DE (1) DE69020060D1 (en)
IE (1) IE902699A1 (en)

Families Citing this family (72)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5149705A (en) * 1987-03-13 1992-09-22 Allergan, Inc. Acetylenes disubstituted with a heteroaromatic group and a tetralin group and having retinoid like activity
US5602130A (en) * 1987-03-20 1997-02-11 Allergan Disubstituted acetylenes bearing heteroaromatic and heterobicyclic groups having retinoid like activity
US5234926A (en) * 1987-03-20 1993-08-10 Allergan, Inc. Disubstituted acetylenes bearing heteroaromatic and heterobicyclic groups having retinoid like activity
US5264578A (en) * 1987-03-20 1993-11-23 Allergan, Inc. Disubstituted acetylenes bearing heterobicyclic groups and heteroaromatic or phenyl groups having retinoid like activity
US5068252A (en) * 1989-07-26 1991-11-26 Allergan, Inc. Methods of using phenylethenyl compounds having retinoid-like activity
US5162546A (en) * 1989-09-19 1992-11-10 Allergan, Inc. Acetylenes disubstituted with a phenyl group and a 2-substituted chromanyl, thiochromanyl or 1,2,3,4-tetrahydroquinolinyl group having retinoid-like activity
US5248777A (en) * 1989-09-19 1993-09-28 Allergan, Inc. Process and intermediates for preparing compounds having a disubstituted acetylene moiety and retinoic acid-like biological activity
US5183827A (en) * 1989-09-19 1993-02-02 Allergan, Inc. Acetylenes disubstituted with a heteroaromatic group and a 2-substituted chromanyl, thiochromanyl or 1,2,3,4-tetrahydroquinolinyl group having retinoid-like activity
US5053523A (en) * 1989-09-19 1991-10-01 Allergan, Inc. Ethynyl-chroman compounds
US5399561A (en) * 1989-09-19 1995-03-21 Allergan, Inc. Acetylenes disubstituted with a phenyl or heteroaryl group and a 2-oxochromanyl, 2-oxothiochromanyl or 2-oxo-1,2,3,4-tetrahydro-quinolinyl group having retinoid-like biological activity
US5272156A (en) * 1989-09-19 1993-12-21 Allergan, Inc. Acetylenes disubstituted with a heteroaromatic group and a 2-substituted 1,2,3,4-tetrahydroquinolinyl group having retinoid-like activity
US5175185A (en) * 1989-12-29 1992-12-29 Allergan, Inc. Acetylenes disubstituted with a heteroaromatic group and a substituted phenyl group having retinoid like activity
US5264456A (en) * 1989-12-29 1993-11-23 Allergan, Inc. Acetylenes disubstituted with a furyl group and a substituted phenyl group having retinoid like activity
US5202471A (en) * 1990-02-06 1993-04-13 Allergan, Inc. Alkyl, alkoxy and thioalkoxy substituted diphenyl acetylenes having retinoid like activity
DE69214632T2 (en) * 1991-02-13 1997-05-28 Allergan Inc 7-PHENYLETHYNYL-SUBSTITUTED CHROMANE AND THIOCHROMANE WITH RETINOID-LIKE BIOLOGICAL ACTIVITY
CA2105379A1 (en) * 1991-03-26 1992-09-27 Roshantha A. S. Chandraratna Chromans and thiochromans with heteroarylethynyl substituents at the 7-position having retinoid-like biological activity
US5134159A (en) * 1991-03-26 1992-07-28 Allergan, Inc. 7-chromanyl esters of phenols and benzoic acids having retinoid-like activity
JP3499553B2 (en) * 1992-02-11 2004-02-23 アラーガン、インコーポレイテッド Heteroaryl-substituted phenylethenyl compounds with retinoid-like biological activity
US5326898A (en) * 1992-02-11 1994-07-05 Allergan, Inc. Substituted phenylethenyl compounds having retinoid-like biological activity
US5324840A (en) 1992-06-11 1994-06-28 Allergan, Inc. Method of treatment with compounds having retinoid-like activity and reduced skin toxicity and lacking teratogenic effects
US6172115B1 (en) 1993-02-11 2001-01-09 Allergan Sales, Inc. Method for preventing onset of restenosis after angioplasty employing an RXR-specific retinoid
US5455265A (en) 1993-02-11 1995-10-03 Allergan, Inc. Method of treatment with compounds having selective agonist-like activity on RXR retinoid receptors
US5399586A (en) * 1993-03-11 1995-03-21 Allergan, Inc. Treatment of mammals afflicted with tumors with compounds having RXR retinoid receptor agonist activity
US5344959A (en) * 1993-05-18 1994-09-06 Allergan, Inc. Tetrahydronaphthyl and cyclopropyl substituted 1,3-butadienes having retinoid-like activity
US5475022A (en) * 1993-10-18 1995-12-12 Allergan, Inc. Phenyl or heteroaryl and tetrahydronaphthyl substituted diene compounds having retinoid like biological activity
US5470999A (en) * 1993-12-30 1995-11-28 Allergan, Inc. Cyclohexene and bicyclic aromatic substituted ethyne compounds having retinoid-like biological activity
US5426118A (en) * 1993-12-30 1995-06-20 Allergan, Inc. [4-(1,2-epoxycyclohexanyl)but-3-en-1-ynyl]aromatic and heteroaromatic acids and derivatives having retinoid-like biological activity
US5451605A (en) * 1993-12-30 1995-09-19 Allergan, Inc. 1,2-epoxycyclohexanyl and bicyclic aromatic substituted ethyne compounds having retinoid-like biological activity
US5498755A (en) * 1994-08-23 1996-03-12 Chandraratna; Roshantha A. Disubstituted aryl and heteroaryl imines having retinoid-like biological activity
US5556996A (en) * 1994-12-29 1996-09-17 Allergan Oxiranyls disubstituted with a phenyl group and a substituted chromanyl or tetrahydroquinolinyl group having retinoid like activity
US5543534A (en) * 1994-12-29 1996-08-06 Allergan Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl or heteroaryl groups having retinoid-like biological activity
US5534641A (en) * 1994-12-29 1996-07-09 Allergan Acetylenes disubstituted with 2-tetrahydropyranoxyaryl and aryl or heteroaryl groups having retinoid-like biological activity
US5618943A (en) * 1994-12-29 1997-04-08 Allergan Acetylenes disubstituted with a 5 OXO substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity
US5489584A (en) * 1994-12-29 1996-02-06 Allergan, Inc. Acetylenes disubstituted with a 5-amino or substituted 5-amino substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity
US5618931A (en) * 1994-12-29 1997-04-08 Allergan Acetylenes disubstituted with a 5 substituted dihydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity
US5599967A (en) * 1994-12-29 1997-02-04 Allergan Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl of heteroaryl group having retinoid-like biological activity
US5514825A (en) * 1994-12-29 1996-05-07 Allergan, Inc. Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity
US5648514A (en) * 1994-12-29 1997-07-15 Allergan Substituted acetylenes having retinoid-like biological activity
US6025388A (en) * 1995-04-26 2000-02-15 Allergan Sales, Inc. Method for inhibiting gene expression promoted by AP1 protein with RARβ selective retinoids and method for treatment of diseases and conditions with such retinoids
US5616712A (en) * 1995-05-16 1997-04-01 Allergan Acetylenes disubstituted with a phenyl or heteroaryl group and a 2-thio-1,2,3,4-tetrahdroquinolinyl, 2-alkylthio-3,4-dihydroquinolinyl or 2-alkoxy-3,4-dihydroquinolinyl group having retinoid-like biological activity
US5917082A (en) * 1995-06-06 1999-06-29 Allergan Sales, Inc. 2,4-pentadienoic acid derivatives having retinoid-like biological activity
US5675033A (en) * 1995-06-06 1997-10-07 Allergan 2,4-pentadienoic acid derivatives having retinoid-like biological activity
FR2735371B1 (en) * 1995-06-19 1997-07-18 Cird Galderma METHOD FOR IDENTIFYING RAR RECEPTOR ANTAGONIST COMPOUNDS
US6008204A (en) 1995-09-01 1999-12-28 Allergan Sales, Inc. Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities
US6218128B1 (en) 1997-09-12 2001-04-17 Allergan Sales, Inc. Methods of identifying compounds having nuclear receptor negative hormone and/or antagonist activities
US5952345A (en) 1995-09-01 1999-09-14 Allergan Sales, Inc. Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities
US5958954A (en) * 1995-09-01 1999-09-28 Allergan Sales, Inc. Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities
US6942980B1 (en) 1995-09-01 2005-09-13 Allergan, Inc. Methods of identifying compounds having nuclear receptor negative hormone and/or antagonist activities
AU7598596A (en) * 1995-11-01 1997-05-22 Allergan, Inc. Sulfides, sulfoxides and sulfones disubstituted with a tetrahydronaphthalenyl, chromanyl, thiochromanyl or tetrahydroquinolinyl and substituted phenyl or heteroaryl group, having retinoid-like biological activity
US5675024A (en) * 1995-11-22 1997-10-07 Allergan Aryl or heteroaryl amides of tetrahydronaphthalene, chroman, thiochroman and 1,2,3,4,-tetrahydroquinoline carboxylic acids, having an electron withdrawing substituent in the aromatic or heteroaromatic moiety, having retinoid-like biological activity
US5663357A (en) * 1995-11-22 1997-09-02 Allergan Substituted heteroarylamides having retinoid-like biological activity
US5965606A (en) 1995-12-29 1999-10-12 Allergan Sales, Inc. Methods of treatment with compounds having RAR.sub.α receptor specific or selective activity
US5688957A (en) * 1995-12-29 1997-11-18 Allergan (3"-thioxacyclohex-1"-enyl)!-but-3'-ene-1'-ynyl!aryl and (3"-thioxacyclohex-1"-enyl)!-but-3'-ene-1'-ynyl!heteroaryl carboxylic acids and esters having retinoid-like biological activity
US20030219832A1 (en) * 1996-03-11 2003-11-27 Klein Elliott S. Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities
US5763635A (en) * 1996-06-21 1998-06-09 Allergan Tetrahydronaphthalene derivatives substituted in the 8 position with alkyhidene groups having retinoid and/or retinoid antagonist-like biological activity
US5747542A (en) * 1996-06-21 1998-05-05 Allergan Oxo-substituted tetrahydronaphthalene derivatives having retinold and/or retinoid antagonist-like biological activity
US5741896A (en) 1996-06-21 1998-04-21 Allergan O- or S- substituted tetrahydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity
US5808124A (en) * 1996-06-21 1998-09-15 Allergan O- or S-substituted dihydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity
US5723666A (en) * 1996-06-21 1998-03-03 Allergan Oxime substituted tetrahydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity
US5773594A (en) 1996-06-21 1998-06-30 Allergan Alkyl or aryl substituted dihydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity
US6555690B2 (en) 1996-06-21 2003-04-29 Allergan, Inc. Alkyl or aryl substituted dihydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity
US5739338A (en) * 1996-11-05 1998-04-14 Allergan N-aryl substituted tetrahydroquinolines having retinoid agonist, retinoid antagonist or retinoid inverse agonist type biological activity
US5728846A (en) * 1996-12-12 1998-03-17 Allergan Benzo 1,2-g!-chrom-3-ene and benzo 1,2-g!-thiochrom-3-ene derivatives
US5760276A (en) * 1997-03-06 1998-06-02 Allergan Aryl-and heteroarylcyclohexenyl substituted alkenes having retinoid agonist, antagonist or inverse agonist type biological activity
US6037488A (en) 1997-04-19 2000-03-14 Allergan Sales, Inc. Trisubstituted phenyl derivatives having retinoid agonist, antagonist or inverse agonist type biological activity
US5919970A (en) 1997-04-24 1999-07-06 Allergan Sales, Inc. Substituted diaryl or diheteroaryl methanes, ethers and amines having retinoid agonist, antagonist or inverse agonist type biological activity
US6515124B2 (en) 2000-02-09 2003-02-04 Hoffman-La Roche Inc. Dehydroamino acids
US6313107B1 (en) * 2000-08-29 2001-11-06 Allergan Sales, Inc. Methods of providing and using compounds having activity as inhibitors of cytochrome P450RAI
US6387951B1 (en) 2000-08-29 2002-05-14 Allergan Sales, Inc. Compounds having activity as inhibitors of cytochrome P450RAI
US6369261B1 (en) 2000-08-29 2002-04-09 Allergan Sales, Inc. Compounds having activity as inhibitors of cytochrome P450RAI
AU2002319677B8 (en) * 2001-07-23 2009-04-30 Atwater Management Llc Cytoprotective compounds, pharmaceutical and cosmetic formulations, and methods
GB0915196D0 (en) 2009-09-01 2009-10-07 King S College London Therapeutic compounds and their use

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4326055A (en) * 1977-12-22 1982-04-20 Hoffmann-La Roche Inc. Stilbene derivatives
DE3475305D1 (en) * 1983-07-05 1988-12-29 Pfizer Carboxylic acid derivatives useful for inhibiting the degradation of cartilage
FR2562539B1 (en) * 1984-04-06 1987-04-17 Chauvin Blache Lab NOVEL VINYL-4 BENZOIC ACID DERIVATIVES, PREPARATION METHOD THEREOF AND THERAPEUTIC APPLICATIONS THEREOF AND AS LIGANDS
JPS6122046A (en) * 1984-07-07 1986-01-30 Koichi Shiyudo Stilbene derivative
GB2163159B (en) * 1984-08-13 1987-10-14 Oreal 1-substituted derivatives of 4-methoxy-2, 3, 6-trimethylbenzene, process for their preparation and medicinal and cosmetic compositions containing them
LU85544A1 (en) * 1984-09-19 1986-04-03 Cird AROMATIC HETEROCYCLIC DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATION IN THE THERAPEUTIC AND COSMETIC FIELDS
DE3434946A1 (en) * 1984-09-22 1986-04-03 Basf Ag, 6700 Ludwigshafen DIARYLACETYLENE, THEIR PRODUCTION AND USE
US4739098A (en) * 1986-09-22 1988-04-19 Allergan, Inc. Ethynylphenyl-containing retinoic acid derivatives
US4810804A (en) * 1987-03-26 1989-03-07 Allergan, Inc. Acetylenes disubstituted with a phenyl group and a heterobicyclic group having retinoid-like activity

Also Published As

Publication number Publication date
DE69020060D1 (en) 1995-07-20
EP0410742A1 (en) 1991-01-30
AU5979090A (en) 1991-01-31
US4992468A (en) 1991-02-12
EP0410742B1 (en) 1995-06-14
AU638037B2 (en) 1993-06-17
JPH0381240A (en) 1991-04-05
IE902699A1 (en) 1991-02-27
ATE123754T1 (en) 1995-06-15

Similar Documents

Publication Publication Date Title
CA2020253A1 (en) Phenylethenyl compounds having retinoid-like activity
US5068252A (en) Methods of using phenylethenyl compounds having retinoid-like activity
US4739098A (en) Ethynylphenyl-containing retinoic acid derivatives
US5202471A (en) Alkyl, alkoxy and thioalkoxy substituted diphenyl acetylenes having retinoid like activity
US5326898A (en) Substituted phenylethenyl compounds having retinoid-like biological activity
US5434173A (en) Heteroaryl substituted phenylethenyl compounds having retinoid-like biological activity
US5470999A (en) Cyclohexene and bicyclic aromatic substituted ethyne compounds having retinoid-like biological activity
EP0337689B1 (en) Tetralin esters of phenols or benzoic acids having retinoid like activity
US5231113A (en) Tetralin esters of phenols or benzoic acids having retinoid like activity
US5344959A (en) Tetrahydronaphthyl and cyclopropyl substituted 1,3-butadienes having retinoid-like activity
US5264456A (en) Acetylenes disubstituted with a furyl group and a substituted phenyl group having retinoid like activity
US5175185A (en) Acetylenes disubstituted with a heteroaromatic group and a substituted phenyl group having retinoid like activity
US5013744A (en) Acetylenes disubstituted with a pyridinyl group and a substituted phenyl group having retinoid like activity
US5648503A (en) Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity
JP4052668B2 (en) 2,4-pentadienoic acid derivatives having retinoid-like biological activity
US4980369A (en) Acetylenes disubstituted with a phenyl group and a 2-substituted chromanyl or thiochromanyl group having retinoid-like activity
US5556996A (en) Oxiranyls disubstituted with a phenyl group and a substituted chromanyl or tetrahydroquinolinyl group having retinoid like activity
EP0273451B1 (en) Lipoxygenase inhibitory compounds
JPS63264578A (en) Disubstituted acetylene with retinoid-like activity
PL168679B1 (en) Method of obtaining novel chromates and thiochromates of activity similar to that of retidiones

Legal Events

Date Code Title Description
FZDE Discontinued